Fusion of HIV-1 with host cells requires certain fusion "coreceptors" in addition to CD4, the primary receptor for HIV-l. The chemokine receptor CCR5 was recently shown to be the predominant fusion coreceptor utilized by HIV-l both during transmission and throughout the early stages of infection, when therapeutic interventions have proven most successful. Because it plays a central role in mediating HIV-l transmission and pathogenesis but appears to be non-essential for human health, CCR5 provides an attractive new target for antiviral drug development. In preliminary testing, the anti-CCR5 monoclonal antibody PA14 has demonstrated potent antiviral activity but limited effects on CCR5's physiologic activity. The overall goal of this Phase I project is to evaluate the therapeutic potential of PA14 using the best available in vitro and in vivo models of HIV-l infection. This Phase I project will examine the breadth and potency of PA14's antiviral activity in vitro using a spectrum of genotypically and geographically diverse primary HIV-l isolates. PA14's antiviral activity in vivo will be examined in both therapeutic and prophylactic settings using the hu-PBL-SCID mouse model of HIV-1 infection. Lastly, PAl4-resistant viruses will be generated in vitro and in vivo and characterized for their coreceptor usage patterns. In the Phase II project, humanized forms of PA14 will be produced and further evaluated for safety and efficacy in highly relevant SHIV-macaque models of HIV-1 infection as a prelude to human clinical trials of this agent. If successful, this project will provide important milestones in the development of a new class of antiviral agents that target HIV-l fusion coreceptors. PROPOSED COMMERCIAL APPLICATION: This project seeks to develop a promising new HIV-l therapeutic agent that has a novel mode of action. For a drug that safely and effectively blocks a new step of the HIV-l replicative cycle, the market would be HIV+ individuals who are suboptimally treated by existing therapies. These individuals would include those with measurable viral loads despite highly active antiretroviral therapy or and those who experience significant treatment toxicities. Currently, these individuals comprise a significant if not majority fraction of HIV seropositive individuals, who number approximately 900,000 in the U.S.